BICYCLO[2.2.2]OCTENES.
v
J. Org. Chem., Vol. 37, No. 18,i979
2871
Studies with Bicyclo[Z,Z.2]octenes. V.l The Total Synthesis of (*)-Patchouli Alcohol ROBERTN. MIRRINGTOX* AND KARLJ. SCHMALZL~ Department of Organic Chemistry, University of Western Australia, Nedlands, W . A . 6009, Australia Received January 18, l97a A stereospecific total synthesis of (&)-patchouli alcohol (2) via the key intermediate alcohol 14a is described. A modified Reformatsky procedure was used to convert ketone 4 in high yield into a mixture of the conjugated esters 9a and loa without concurrent formation of nonconjugated esters. Dissolving metal reduction of the conjugated esters gave alcohols 14a and 15a (4: l), whose relative configurations were readily assigned by pmr spectroscopy. The sequence was completed via the intermediates 14c, 16, 18a, 18c, and 18e.
Patchouli alcohol and seychellene are two tricyclic sesquiterpenes which have been isolated from patchouli oil, an important raw material for the composition of perfumes. Patchouli alcohol has been the subject of a large volume of both degradative and synthetic work, the most recent of which, up to the commencement of our work, was that of Buchi and coworker^.^-^ The original structure 1 which Buchi attempted to synthesize was, however, incorrect, and it was only by a fortuitous rearrangement in the final steps of the synthesis that he arrived a t patchouli alcohol, which was later shown to have a different structure (2) by X-ray investigations.' It was this ambiguity which led us to design a more direct synthesis of the revised structure based on bicyclo [2.2.2]octene intermediates.
14a
J
I
16
1
1 patchouli alcohol 1
2 3 (-)-patchouli alcohol (-) -seychellene
The hydrocarbon seychellene (3) was isolated recently by Ourisson and Wolff* from patchouli oil obtained from the Seychelles Islands. The similarity in structure between seychellene and patchouli alcohol suggested a synthet'ic route to seychellene utilizing intermediates which had previously been prepared for the synthesis of pat'chouli alcohol. The crucial intermediate in bot'h syntheses was the olefin 14a. The plan involved the modification of the olefinic bridge of this compound to yield a bicyclo[2.2.2]octanone 16 with the ketone function a t Cz for patchouli alcohol, and a bicyclo [2.2.2]octanone with the ketone at Ca for seychellene. This paper describes the synthesis of (*)-patchouli alcohol, while the accompanying paperg outlines details of the synthesis of ( &)-seychellene. (1) P a r t I V : R. P. Gregson, R . N. hlirrington, and K . J. Schmalzl, - 4 ~ 3 t . 531 (1972). (2) (a) Abstracted in p a r t from the P h . D . thesis of K. J. Schmalzl, University of Western Australia. M a y 1971. (b) T h e award of a Common-
J. Chem., 28,
wealth Postgraduate Scholarship t o K. J. S.is gratefully acknowledged. (3) G. Btichi a n d R . E. Erickson, J . Amer. Chem. Soc., 78, 1262 (1956). (4) G. Blichi, R . E. Erickson, and N . Wakabayashi, i b i d . , 83, 927 (1961). (5) G . Btichi and W.D. MacLeod, Jr., i b i d . , 84, 3205 (1962). ( 6 ) G. Btichi, W. D . MacLeod, Jr., a n d J. Padilla O., i b i d . , 86, 4438 (1964).
(7) M . Dobler, J. D . Dunits, E. Gubler, H. P. Weber, G. Btichi, and J. Padilla O., Proc. Chem. Soc., 383 (1963). ( 8 ) G. Wolff a n d G. Ourisson, Tetrahedron, 25, 4903 (1969). (9) R . N . 3Iirrington a n d K. ,J. Schmalsl, J . O r g . Chem., 37, 2877 (1972).
seychellene
Results and Discussion Entry into the bicyclo [2.2.2]octane ring system was gained via the Diels-Alder reaction of 1,3-dimethyll13-cyclohexadiene with met'hyl vinyl ketone to give ketone 4 as the major product,1° whose structure and stereochemistry have been rigorously established. The conversion of 4 to t'he planned intermediate 14a appeared to be a simple task in theory, since a wide variet'y of methods are available for extending carbon chains by a two-carbon fragment.ll The immediate objective was thus a simple and effective method of preparing the conjugated esters 9a and/or 10a from the ketone 4. The Wadsworth-Emmons methodlZ proved disappointing, since only low yields of conjugated esters were obtained, together wit'h a high proportion of starting material. Similarly, other workers13 have found that many ketones, including a substituted pregnan-2O-one, were inert to Lhe Wadsworth-Emmons reagent; this was attributed t o the stringent steric requirements of the reagent. On t'he other hand, it was gratifying to find that the @-hydroxy ester 6 could be obtained consistently in (10) R . N. Mirrington a n d K. J . Schmalzl, i b i d . , 34,2358 (1969). (11) See H. 0. House, "Modern Synthetic Reactions," 1%'. A . Benjamin, New York, N. Y . , 1965, Chapter 8 , for many leading references. (12) W.S.Wadsworth, Jr., and W. D . Eminons, J . Amer. Chem. Sac., 83, 1733 (1961). (13) A. K.Bose and R. T. Dahill, Jr.,
J. Org. Chem.,
SO, 505 (1965).
2872 J . Org. Chem., Vol. 37, No. 18, 1972
4
5, R = ZnBr 6, R = H
7, R=COCH,
8
yields of up to 90% via the Reformatsky reaction on the ketone 4. The difficulty with this approach soon became apparent, however, when attempted dehydration of the @-hydroxyester by a number of the usual methods under acidic conditions resulted in rearrangement of the bicyclo [2.2.2]octene skeleton to an aromatic compound. Some aspects of this rearrangement and of its mechanism have been reported in an earlier paper.'
H
9a, R = E t b, R = H
11
lba, R = E t b, R = H
12
Dehydration of 6 without rearrangement was accomplished using phosphorus oxychloride in pyridine. The conjugated esters 9a and 10a were obtained, contaminated with the nonconjugated ester 11. The other P,y-unsaturated ester 12 was not detected, and this was not unexpected as there would be serious A(ls3) between the C1 methyl group and the substituents on the exocyclic double bond. The preparation of conjugated esters by dehydration of &hydroxy esters16 has this obvious weakness in the general case, since significant quantities of the nonconjugated esters are usually formed. The product of the Reformatsky reaction was itself of some interest, because it might have been expected that a mixture of the 9R and 9 s epimers of 6 would have (14) F. Johnson and S. K. Malhotra, J . Amer. Chem. Soc., 87, 5492 (1965). (15) F. Johnson, Chem. Reu., 68, 375 (1968). (16) R . 1,. Shriner, Org. React., 1, 1 (1942).
MIRRINGTON AND SCHAIALZL been obtained. It appeared, however, that only one, or certainly predominantly one epimer was formed, but no positive identification has been possible. This question was not pursued further a t the time as it obviously had little or no bearing on the structure of the conjugated esters 9a and 10a obtained from 6,either by dehydration or by acetylation and elimination (see below). I n view of the problems associated with the dehydration of the hydroxy ester 6, an alternative procedure was designed involving acetylation of the tertiary alcohol and subsequent elimination of acetic acid from the acetate 7 by base, to yield the conjugated esters 9a and 10a e x c l u ~ i v e l y . ~The ~ acetate 7 was obtained in good yield from the hydroxy ester 6 using acetyl chloride and N,N-dimethylaniline. l8 An alternate and more convenient procedure was to treat the Reformatsky complex 5 directly with acetyl chloride and N ,N-dime t hylaniline. The acetate 7 was readily converted to a mixture of the conjugated 2 and E esters 10a and 9a by elimination of acetic acid with sodium ethoxide. A variety of other bases were tried, including sodium hydride, potassium tert-butoxide, and even basic alumina. Sodium ethoxide mas found to be the most convenient and would be especially useful when the conjugated esters were prone to isomerization under strongly basic conditions. Even in cases where the P,y-unsaturated esters were more stable than the a,@-unsaturatedesters, the latter could be formed almost exclusively by this method.I7 This observation, together with the simplicity of the procedure and low cost of the reagents, make this a very useful high-yielding method for large-scale preparation of a,@-unsaturatedesters via the Reformatsky reaction,lg particularly in view of the great variety of ketones reactive undei Reformatsky conditions. l6 The conjugated esters 9a and IOa were easily distinguished by their pmr spectra. The characteristic signals were due to H6 and the C 9vinyl methyl group. In the 2 ester 10a there was strong deshielding of H6 by the coplanar carboxyl group. This signal, a doublet of doublets, mas obscured by the quartet of the ester resonance in loa, but was clearly visible in the spectrum of the corresponding 2 acid 10b at 4.05 ppm. The signal for H6in the pmr spectrum of the E acid 9b was situated much further upfield at 2.27 ppm as expected, since the carboxyl group was now remote from H6. The strong deshielding of H6 in the 2 ester and acid also indicated that the preferred conformation was as shown, since rotation about the C6-Cg bond to alternative conformations would not be expected to give rise to such a strong deshielding effect on Ha. In addition, other conformations would be unlikely because of prohibitive steric interactions between either the ester group or the C, methyl group and other functions in the molecule. (17) K H Fung K J Schmalsl and R X Mirnngton, Tetrahedron L e t t , 5017 (1969) (18) J. D Cocker and T G Halsall, I. Chem Soc , 4262 (1956) (19) Since t h e completion of this section and the subsequent appearance of our communication,17 a similar procedure has been reported b y Engel, et al ,20 uaing steroidal substrates This procedure is analogous t o t h a t of Linstead, et al , 2 1 mho used aqueous bases t o obtain conjugated aczds from Pacyloxy esters (20) C R Engel, V S Salvi, and L. Ruefit, Can I Chem ,48,3426(1970) (21) R P Linstead, L N O n e n , and R F Webb, J Chem S o c , 1211 (1953)
BICYCLO [2.2.2] OCTENES.
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J . Org. Chem., Vol. 37, No. 18,1076 2873
Further evidence for the preferred conformation of both the 2 and E esters was obtained from the chemical shifts of the C9 vinyl methyl doublets. I n the 2 ester 10a there was strong shielding of this methyl to 6 1.57 by the olefinic bridge. In the E ester 9a this shielding effect was counteracted by the strong deshielding effect of the coplanar carboxyl group so that the net effect was to shift the signal to 6 1.92. An alternative preferred conformation for the E ester, obtained by rotating the side chain around the Cs-Cg bond through 180°, was unlikely, since no strong shielding of the Clo olefinic proton was observed. In fact, the Clo olefinic proton signals of the 2 and E esters both occurred near 5.5 ppm. This value is very similar to that of the olefinic proton signals in the pmr spectra of the conjugated esters ethyl P,P-diethylacrylate and ethyl cyclohexylideneacetate, obtained from diethyl ketone and cyclohexanone, respectively." Reduction of the conjugated esters 9a and 10a with lithium in ammonia and ethanol yielded the alcohols 14a and 15a in a ratio of 4:1, respectively. This ratio could be accounted for by consideration of the two most likely conformations 13a and 13b of the intermediate radical anion (only one canonical form represented). The conformer 13b would be somewhat lcss preferred than 13a because the steric interaction of the T cloud of the olefinic bridge with the protons of the freely rotating Cg methyl group in 13a should be less severe than with the rigidly fixed HIo in 13b. If protonation of the radical anion a t Cg were mainly occurring from the less hindered side (remote from the C1 methyl group), 13a would give 14a while 13b would give 15a. The most important single factor determining the success of the synthesis of patchouli alcohol as well as of seychelleneg was the ability to distinguish these two epimers 14a and 15a,and the finding that the major one had the desired stereochemistry.
ture, except in the most trivial cases, must be regarded with great caution and always raises the question of rearrangement. The pmr spectrum of the alcohol of minor abundance, however, showed all the characteristic signals of the bicyclo [2.2.2]octene skeleton and, furthermore, apart from the position of the Cgmethyl doublet, these signals were virtually superimposable on those of the major epimer 14a. The methyl doublet of the minor epimer was more shielded than that of the major epimer (0.55 ppm compared to 0.78 ppm) and we have observed as expected2*that in all cases where the side chain was endo to the olefinic bridge, the pmr signals were strongly shielded relative t o signals in the corresponding exo isomers. It was inconceivable, therefore, that the minor epimer with the highly shielded Cgmethyl group could have an exo side chain. I n addition, hydrochlorination of the acetate 15b caused a downfield shift of the Cg methyl doublet in the pmr spectrum, confirming that the shielding effect was due to the olefinic bridge. The major epimer 14a was also shown to have its side chain endo when the system was cyclized in the final steps of the synthesis. I n short, no epimerization about C6or rearrangement had occurred during the reduction, and the two anticipated products 14a and 15a were obtained. It was the simple observation of the difference in chemical shift of the Cs methyl doublets which formed the basis of the assignment of stereochemistry to the major and minor epimers. If both alcohols 14a and 15a were to adopt that conformation which minimized the lj3-diaxial-like interactions with the methyl group a t C1, the Cg methyl would be close to the olefinic bridge in 15a, whereas in 14a it would be much more remote. It was then apparent that the major epimer with the less shielded Cgmethyl signal in its pmr spectrum was 14a, which had the stereochemistry required for the synthesis of (=k)-patchouli alcohol and (A)seychellene. This large difference in the chemical shift of the Cg methyl doublets was quite consistent, regardless of the function a t the end of the side chain (Table I), alTABLE I CHEMICAL SHIFTS"OF Ce METHYL GROUPS
13a
13b
Compd
C8 methyl doubletb
Compd
Ce methyl doubletb
DifferenceC
0.78 15a 0.55 0.23 14bd 0.81 15bd 0.57 0.24 14c 0.62 15c 0.48 0.14 16 0.67 17 0.50 0.17 a Measured for CCL solutions on a Varian A-60 spectrometer. Chemical shifts in parts per million downfield from TMS as internal standard. b J = 6.5 Hz. Parts per million. d The preparation and spectral properties of this compound appear in the accompanying paper.0 14a
14
15 a, R = H
b, R = A c C,
R=C(Ph),
The reduction was usually carried out on a mixture of Z and E esters. To eliminate the very remote possibility that the Z ester was yielding 15a almost ex-
clusively, while the E ester was yielding 14a, the reduction was also carried out on pure E ester 9a. The ratio of products 14a and 15a obtained was unchanged. Isolation of a minor product from any reaction mix-
though with triphenylmethyl (trityl) ethers the difference was significantly smaller. The effect was similar when either the olefinic bridge or the carbonyl group a t Cz was the shielding function. The trityl ether 14c was treated with diborane in tetrahydrofuranz3 and the organoborane was oxidized (22) I. Botioa. and R. N. Mirrington, Aust. J . Chem , 8 4 , 1467 (1971), and references cited therein; A. A. Othman, M. A. Qasseem, and N . A. J. Rogers, Tetrahedron, a3, 87 (1967). (23) G. Zweifel and H. C . Brown, Org. React., 13, 1 (1963).
MIRRINGTON AND SCHIIALZL
2874 J . Org. Chem., VoL 37, No. 18, 1972
directly with chromium trioxide-pyridine to yield the ketone 16. This direct procedure not only saved time and material but was also found to be necessary in the present case. -\/luch difficulty was experienced in the oxidation of the organoborane to the intermediate alcohol with aqueous alkaline hydrogen peroxide because of the extreme insolubility of the trityl ether in the reaction medium. Orgarioboranes have been oxidized directly before using chromic but this method is obviously not applicable to the oxidation of acid-sensitive systems. It was found that chromium trioxide-pyridine could be used without any complications; this method could be of general applicability especially with water-insoluble compounds.
LerouxZ6in the cyclization of 7-halo ketones to the corresponding cyclobutanols. However, the iodide 18e was found to be completely inert t o magnesium. Prolonged heating with magnesium in tetrahydrofuran, even on addition of equimolar amounts of mercuric chloride,26 resulted in recovery of the iodide unchanged. Similarly, the bromide 18f was found by DanishefskyZ7 to be inert to magnesium. The iodide 18e was successfully cyclized using sodium in tetrahydrofuran a t 100" in a sealed tube. The two products isolated were (&)-patchouli alcohol (2) and the acyclic ketone 18g. These rcsults are in agreement with those of Danishefsky and Dumas, who cyclized the bromide 18f to (*)-patchouli alcohol using similar
condition^.^^ The reasons for the inertness of 18e and 18f to the action of magnesium are not clear at present. Further studies of the scope and mechanism of this interesting intramolecular cyclization28using various reagents and substrates are currently in progress in this laboratory. 16
17
19
18
a, Z = O H b, Z = O C ( P h ) , C,
Z=OTs
e, Z = I f, Z = B r g, Z = H
d, Z = O C O N H P h
The relative stereochemistry of the C3 methyl group in the ketone 16 was assigned as depictcd, since one would anticipate exclusive attack of diborane from the less hindered sidez3of the olefin 14c, and the above oxidation conditions should not cause epimerization. I n any case this stereochemistry was not vital, since alkylation in the next step destroyed the asymmetric center at C3. Potassium triphenylmethide was found to be a vastly superior base to sodium hydride or potassium tert-butoxide for the alkylation of the ketone 16. The ketone was converted quantitatively by titration t o its enolate anion, which reacted rapidly with methyl iodide at 20". The usual objection to the use of potassium triphenylmethide as the base in alkylation reactions is the difficulty in separation of the alkylated ketones from the triphenylmethane produced in the titration.2j This was not a problem in the present case, because the ketone 18b was not isolated, but converted to the alcohol 18a by hydrogenolysis of the trityl ether function. Chromatography at this stage of the synthesis readily separated the triphenylmethane formed in the titration and in the hydrogenolysis from the alcohol 18a. The tosylate 18c, prepared in the usual way, was converted to the,iodide 18e by treatment with sodium iodide in acetone. Magnesium metal was used with great success by (24) H C. Brown and C. P.Garg, J . Amer. Chem. S o c , 83, 2951 (1961). ( 2 s ) €1 0 House, "Modern Synthetic Reactions," W .-1.Benjamin, ?;en York, N Y , 1965, pp 188-189
Experimental Section Analyses were carried out by the CSIRO Microanalytical Service, Melbourne. Melting points and boiling points are uncorrected; the latter refer to the bath temperature. Infrared spectra were measured on a Perkin-Elmer 337 grating infracord spectrophotometer using carbon tetrachloride solutions. Pmr spectra were measured with a Varian 8-60 spectrometer using carbon tetrachloride solutions unless otherwise specified, with TMS as internal standard. A Varian Serograph Series 1400 gas chromatograph was used for vpc analysis with nitrogen carrier gas a t a flow rate of 15 ml/min. Columns were 5 ft X 0.125 in. of 5% UCON and 570DEGS on nonacid-washed Chromosorb W (80-100 mesh), and 3Y0 SE-30 on Varaport 30 (100-120 mesh). Preparative vpc was carried out using a Wilkens Aerograph Autoprep, Model A-700 with helium as the carrier gas. The aluminum column was 12 ft X 0.375 in. of 10% Carbowax 2031 on non-acid-washed Chromosorb W (44-60 mesh). Reformatsky Reaction with Ketone 4.-Zinc powder (15 g), which had been activated by washing successively with 5% hydrobromic acid, water, ethanol, and acetone and dried at loo", was added t,o a solution of 17 g of the ketone 4 and 24 g of bromoacetic ester in 360 ml of dry benzene. The mixture was stirred and heated, and 0.3 g of iodine was added to initiate the reaction. Stirring and heating were continued so that the mixture refluxed gently for 2 hr after the commencement of the reaction. After cooling, the solution was decanted and the excess sludge of zinc powder was washed with benzene. The zinc complex was destroyed by shaking the combined benzene eolutions with 20y0 aqueous sulfuric acid at, O " , and the benzeiie layer was subsequently washed with 5y0 aqueous sulfuric acid, aqueous sodium carbonate, and water, then dried over anhydrous sodium sulfate. Evaporation of the solvent yielded 23.5 g (927,) of the crude (ester); pmr 6 5.44 hydroxy ester 6: ir 3520 (OH), 1720 (br s, 1, H2), 4.12 (q, J = 7 Hz, 2 , ester), 3.44 (br s, 1, OH), 2.23 (br s, 2 , Clo melhylene), 1.73 (d, J = 1.6 Hz, 3, CSvinyl methyl), 1.27 (t, J = 7 Hz, 3, ester), 1.27 (s, 3, C1 methyl), 0.95 (s, 3, Cg methyl). The analytical sample was prepared by microdistillation, bp 102" (0.1 mm). Anal. Calcd for CMHW OB: C,72.14; H,9.84. Found: C,72.49; H,9.64. Hydrolysis of Hydroxy Ester 6.-A solution of 2 g of the hydroxy ester in 50 ml of 50% aqueous ethanol containing 5 g of sodium hydroxide was refluxed for 43 min. The solution was cooled, acidified with dilute hydrochloric acid at 0 ° , and extracted with ether. The ethereal solution was extracted with aqueous sodium carbonate and, aft,er acidification at 0' with dilute hydrochloric acid, the precipitated organic acid was extracted with et,her. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated t o yield 1.5 g (847,) of the crude crystalline hydroxy acid 8, which crystallized from hexane as colorless prisms: mp (26) I-.Leroux, Bull. Soc. Chirn. F r . , 359 (1968). (27) S . Danishefsky and D . Dumas, Chem. Commun., 1287 (1968). (28) H. 0 . House, J. Riehl, and C. G . Pitt, J . Org. Chem.. 30, 650 (1965).
BICYCLO [2.2.2IOCTENES.
v
134-135"; ir 3525 (OH), 1695 cm-' (acid); pmr (CDCld) 6 6.70 (very br, 2, OH), 5.47 (br s, 1, Hz), 2.46, 2.30 (AB q , J A B = 16 Hz, 2, Clo methylene), 2.30 (br s, 1, H4), 1.75 (d, J = 1.5 Hz, 3, C3 vinyl methyl), 1.30 (s, 3, CI methyl), 1.10 (s, 3, CQ methyl). Anal. Calcd for Cl4H2203: C , 70.55; H , 9.31. Found: C, 70.55; H , 9.38. Dehydration of Hydroxy Ester 6 with Phosphorus Oxychloride in Pyridine.-A solution of 0.9 g of the hydroxy ester in 5 ml of dry pyridine was treated with 1 g of redistilled phosphorus oxychloride, and the solution was stirred for 3 hr a t 60". The reaction mixture was then poured into water and extracted with hexane. The extract was washed with dilute hydrochloric acid and water, then dried over anhydrous sodium sulfate. Evaporation of the solvent yielded 0.63 g of a mixture of the esters ga, lOa,andll,inaratioof ca.3:1:l,respectively,bypmr. The ir and pmr spectra of 9a and 10a are described below. No attempt was made to isolate the nonconjugated ester 11, which gave rise to characteristic pmr signals at 6 4.79 (6, C=CH2), 2.78 (s, CIOmethylene), and 1.00 (s, CI methyl). Acetylation of Hydroxy Ester 6.-A mixture of 5 ml of acetyl chloride, 20 ml of S,N-dimethylaniline (purified l o remove traces of iY-methylaniline), 20 ml of chloroform, and 0.99 g of the hydroxy ester were refluxed for 20 hr. The resultant blue solution was diluted with water, acidified at 0" with dilute hydrochloric acid, and extracted with ether. The ether extract was washed with dilute HC1 and water and dried over anhydrous sodium sulfate, and the solvent was evaporated to yield 1.1 g of the crude acetate, which was purified by rapid chromatography over 30 g of neutral activity I alumina.29 The yield of purified acetate 7 was 0.90 g (787,): ir 1730 cm-I (ester and acetate); pmr 6 5.43 (br s , I, H g ) , 4.06 (q, J = 7 He, 2, ester), 2.69 (s, 2, Clo methylene), 2.28 (br s, 1, H4), 1.91 (s, 3, acetate methyl), 1.75 (d, J = 1.6 Hz, 3, CSvinyl methyl), 1.23 (t, J = 7 Hz, 3, ester), 1.23 (s, 3, tertiary methyl), 1.19 (s, 3, tertiary methyl). The analytical sample was obtained by microdistillation, bp 130" (0.4 mm). Anal. Calcd for ClaH2304: C, 70.10; H , 9.15. Found: C, 69.95; H , 9.23. Modified Acetylation Procedure.-A mixture of 50 g of ketone 4, 58 g of bromoacetic ester, and 45 g of activated zinc powder in 800 ml of dry benzene was treated as previously described and the resultant benzene solution of the zinc complex was decanted. The excess sludge of zinc powder was washed with small portions of dry benzene, and the combined solutions were treated at 0' with 450 ml of purified N,,V-dimethylaniline and 150 ml of acetyl chloride. An immediate blue-black tarry deposit separated and, after stirring for several minutes at 20°, the mixture was heated on a steam bath under gentle reflux overnight. The reaction mixture was then poured into excess dilute HC1 at 0", and the tarry residue was stirred and washed with hexane. The washings were combined with the hexane extract of the acidified reaction mixture and the hexane solution was then washed with dilute HCl, aqueous sodium carbonate, and water and dried over anhydrous sodium sulfate and the solveiit was evaporated to yield 82 g (957,)of the crude acetate 7. Unsaturated Esters 9a and 10a.-The acetate 7 (0.17 g) was treated at 20" with sodium ethoxide solution (0.12 g of sodium in 2 ml of ethanol) for 30 min, the reaction mixture was then poured into water, and the unsaturated esters were extracted with hexane. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to yield 0.12 g (89%) of the mixture of esters 9a and 10a (2.5: 1). In large-scale preparations the crude acetate prepared by the modified acetylation procedure was used without further purification. Treatment of 84 g of acetate with sodium ethoxide solution (14 g of sodium in 400 ml of ethanol) for 80 min at 20" with stirring gave 60 g of the crude unsaturated esters, isolated as above. The esters were separated by chromatography over neutral activity I alumina. The 2 ester 10a was eluted first with hexane: ir 1710 (ester), 1630 cm-1 (conjugated double bond); pmr 6 5.50 (br s, 2, olefinic protons), 4.06 (9, J = 7 Hz, 2, ester) (superimposed on the doublet of doublets for He), 2.32 (br s, 1 , Hd), 1.79 (d, J = 1.6 Hz, 3, C3 vinyl methyl), 1.57 (d, J = 1.2 Hz, 3, COvinyl methyl), 1.24 (t, J = 7 Hz, 3, ester), 0.97 (8,3, CI methyl). The analytical sample was obtained by preparative vpc at 190°, followed bv microdistillation. bD 95' (0.4 mm). Anal. Calcd for Cl6H,4OZ: C, 77.37; H,'9.74. Found: C , 77.52; H , 9.89. (29) T h e grade of alumina was important as the acetate was unstable on basic alumina, from which the only products eluted were unsaturated esters.
J . Org. Chem., Vol. SY,No. 18, i 9 Y g 2875 The E ester 9a was eluted with hexane and hexane-benzene (9:l): ir 1710 (ester), 1630 cm-' (conjugated double bond); pmr 6 5.50 (br s, 2, olefinic protons), 4.05 (q, J = 7 Hz, 2, ester), 2.330(br s, 1, H4), 1.92 (d, J = 1.3 Hz, 3, CQvinyl methyl), 1.81 (d, J = 1.8 Hz, 3, C3 vinyl methyl), 1.23 (t, J = 7 €12, 3, ester), 0.98 (s, 3, C1 methyl). The analytical sample was obtained by preparative vpc at 190", followed by microdistillation, bp 115" (1 mm). Anal. Calcd for CleH24Oz: C, 77.37; H , 9.74. Found: C, 77.21; H , 9.90. Hydrolysis of Esters 9a and loa. A. The E Ester 9a.-A solution of 0.63 g of the ester in 25 ml of 50% aqueous ethanol containing 2 5 g of sodium hydroxide was refluxed for 8 hr. The crude acid 9b (0.53 g, 947,) was isolated in the manner described for 8. The acid crystallized from hexane as colorless prisms: mp 138-139'; ir 1685 (acid), 1625 cm-1 (conjugated double bond); pmr 6 12.11 (br s, 1, OH), 5.60 (br s, 1, Hlo), 5.50 (br s, I, Hz), 2.3430(br s, 1, Hd), 1.93 (br s, 3, Cg vinyl methyl), 1.82 (d, J = 1.8 Ha, 3, Cs vinyl methyl), 1.00 (s, 3, C1 methyl). Anal. Calcd for C14H~002: C, 76.32; H , 9.15. Found: C, 75.93; H , 9.31. B. The Z Ester 10a.--A solution of 0.45 g of the ester in 25 ml of 50% aqueous ethanol containing 2 g of sodium hydroxide was refluxed for 10 hr. The crude 2 acid 10b (0.37 g, 927,) was isolated in the manner described for 8. The acid crystallized from hexane as colorless, flat needles which sublimed readily 011 heating: mp 162-163'; ir 1685 (acid), 1625 cm-l (conjugated double bond); pmr 6 11.62 (br s, 1, OH), 5.61 (9, J = 1.3 H a , 1, H,o), 5.48 (br s, 1, Hz), 4.05 (dd, J 6 , j n Js,a, = 16 Hz, 1, He), 2.33 (br s, 1, H4), 1.80 (d, J = 1.5 Hz, 3, CDvinyl methyl), 1.64 (d, J = 1.3 €Iz, 3, COvinyl methyl), 1.00 (5, 3, CI methyl). Anal. Calcd for ClaHzoOz: C, 76.32; II, 9.15. Found: C, 76.45; H , 9.02. Lithium-Ammonia Reduction of Esters 9a and 10a.-Following the general procedure of Stork and Darling,3117 g of the mixture of esters 9a and loa (2.5: 1) in 200 ml of dry ethanol and 150 ml of ether was added to 1000 ml of liquid ammonia. Lithium metal (11 g) was added in portions with stirring over 1 hr. The blue color persisted throughout the solution for some time after the addition of the last few portions of lithium metal. The ammonia was evaporated by stirring and the cautious addition of water. The aqueous alkaline reaction mixture was extracted with ether. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to yield 13.5 g (947,) of the crude mixture of alcohols 14a and 15a. A portion (7.5 g) was chromatographed on 300 g of neutral activity I alumina, and elution with benzene-ether (9: 1)yielded 4.8 g (607,) of the major epimer 14a: ir 3630, 3430 cni-1 (OH); pmr 6 5.47 (br s, 1, Hs), 3.51 (m, 2, Cll methylene), 2.35 (br s, 1, OH), 2.27 (br s, 1, H4), 1.73 (d, J = 1.7 HL, 3, C3 methyl), 1.08 (s, 3, C1 methyl), 0.78 (d, J = 6.5 Hz, 3, CS methyl). The analytical sample was prepared by microdistilC, 80.71; lation, bp 97" (0.1 mm). Anal. Calcd for C14&0: H , 11.61. Found: C,80.75; H , 11.67. The minor epimer 15a (1.2 g, 15%) was eluted with benxeneether ( 9 : l ) and benzene-ether ( 4 : l ) : ir 3630, 3430 cm-1 (OH);pmr 8 5.46 (br s, 1, Hz), 4.11 (br s, 1, OH), 3.55 (t, J = 7 Hz, 2, CII methylene), 2.27 (br s, 1, H4), 1.73 (d, J = 1.7 Hz,3, CBvinyl methyl), 1.07 (s, 3, C1 methyl), 0.55 (d, J = 6.5 Ha, 3, COmethyl). The analytical sample was obt8ine.d by preparative vpc at 190", followed by microdistillation, bp 100" (0.1 mm). Anal. Calcd for C14H240: C, 80.71; H, 11.61. Found: C,80.95; H , 11.56. Preparation of the Trityl Ether 14c.-A solution of 3.3 g of the alcohol 14a in 50 ml of benzene and 3 ml of pyridine was heated with 6.0 g of trityl chloride under gentle reflux for 5 hr. The solution was cooled to 0" and the crystalline pyridine hydrochloride was filtered by suction. The filtrate was evaporated almost to dryness and the residue was dissolved in hexane and applied to a column of 3CO g of neutral activity I alumina. Elution with hexane and hexane-benzene (4: 1) yielded 6.0 g (85%) of the trityl ether 14c, which crystallized from ethanol as colorless prisms: mp 105-106'; pmr 6 5.47 (br s, 1, H2), 3.02 (m, 2, CII methylene), 2.24 (br s, I , H4), 1.74 (d, J = 1.7 Hz, 3, CS vinyl methyl), 1.15 (s, 3, C1 methyl), 0.62 (d, J = 6.5 Hz, 3, CS methyl). Anal. Calcd for C33H3SO: C, 87.95; H, 8.50. Found: C,88.12; H, 8.48.
+
-
(30) T h e signal for Hs a t about 6 2.2 v a s superimposed on this broad singlet. (31) G . Stork and S.D. Darling, J. Amer. Chem. So?., 86, 1761 (1964)
2876 J . Org. Chern., Vol. 37, No. 18, 1979 A mixture of alcohols 14a and 15a (4: 1) was also tritylated as above, and, in the pmr spectrum of the mixture of trityl ethers 14c and 15c obtained, the characteristic signals of the minor epimer 15c were seen to be 6 1.04 (s, C1 methyl), 0.48 (d, J = 6.5Hz, C~methyl). Hydroboration-Oxidation of Trityl Ether 14c.-Diborane was passed through a stirred solution of 27 g of the trityl ether in 140 ml of dry tetrahydrofuran under nitrogen at 20°,23 until pmr analysis of an aliquot of the reaction mixture showed the complete disappearance of the olefinic signal due to the starting material. Water was then added dropwise to destroy excess hydride. The mixture was then poured into water and the organoborane was extracted with benzene. The solvents were evaporated and the residue was dissolved in 250 ml of pyridine. The pyridine solution was added to chromium trioxide-pyridine complex3*(40 g of chromium trioxide in 400 ml of pyridine) and the mixture was left overnight at 20'. The reaction mixture was then poured into 1500 ml of ether and the red precipitate was filtered by suction and washed several times with ether. The combined filtrate and washings were then shaken with excess 10% hydrochloric acid a t 0" to remove the pyridine. The ether solution was washed exhaustively with dilute HC1 at 0" and then with dilute aqueous sodium carbonate and water, and dried over anhydrous sodium sulfate. Evaporation of solvent yielded the crude ketone 16, which was purified by recrystallization from ethanol. The yield after one recrystallization was 14 g (507,). The ketone crystallized from ethyl acetate as colorless prisms: mp 154-155"; ir 1710 em-1 (ketone); pmr 6 3.02 (m, 2, C11 methylene), 2.15 (br q, J = 7.5 Hz, 1, Ha), 1.10 (d, J = 7.5 Hz, 3, Ca methyl), 1.01 (s, 3, C1 methyl), 0.67 (d, J = 6.5 Hz, 3, CQmethyl). Anal. Calcd for Ca3H3802: C,84.93; H,8.21. Found: C,84.72; H , 8.14. A mixture of the trityl ethers 14c and 15c (4: 1) was converted via hydroboration-oxidation (as above) to a mixture of the ketones 16 and 17. Pmr analysis of the mixture showed the characteristic signals of the minor epimer 17 to be 6 0.90 (s, Ct methyl), 0.50 (d, J = 6.5 Hz, CSmethyl). Preparation of Keto Alcohol 18a.-The ketone 16 (6 g) was dissolved in 100 ml of 1,2-dimethoxyethane (glyme) in a flask sealed with a rubber septum cap. By means of a syringe, potassium triphenylmethide solution, prepared by stirring potassium with triphenylmethane in glyme in a septum-sealed flask,33was added to the ketone until the red color of the triphenylmethide ion just persisted. Methyl iodide (20 ml) was then injected; the solution warmed noticeably: and potassium iodide precipitated immediately. The mixture was left overnight at 20", poured into water, and extracted with ether. The ether extract was washed with water and dried over anhydrous sodium sulfate and the solvent was evaporated to yield the trityl ether 18b, which was of course contaminated with triphenylmethane. The crude product was not purified but was dissolved in 400 ml of ethanol; 1 g of 57, palladium on charcoal was added; and the mixture was shaken under 2.5 atm of hydrogen at 20" for 17 hr. After filtration of the catalyst and evaporation of the ethanol, the product was separated from the triphenylmethane by chromatography over 300 g of neutral activity I alumina. Elution with hexane and hexane-ether (9 : 1) yielded triphenylmethane together with minor amounts of other aromatic products,33while 2.4 g (78%) of the alcohol 18a was eluted with hexane-ether (1: 2) and ether. Vpc analysis shoNred a single peak on 3% SE-30 at 170': ir34 3625, 3480 (OH), 1715 cm-I (ketone); pmr3* S 3.52 (m, 2 , C11 methylene), 3.12 (br s, 1, OH), 1.11 (s, 6, 2 tertiary methyls), 0.93 (s, 3, tertiary methyl), 0.90 (d, J = 6.5 Hz, 3, Cg methyl). The analytical sample was prepared by microdistillation, bp 112" (0.02 mm). Anal. Calcd for Cl&02: C, 75.58; H , 11.00. Found: C, 75.52; H , 10.78. The phenylurethane 18d of this alcohol was prepared in the usual mannera5and crystallized from hexane-benzene as colorless prisms: mp 142-143" (lit.*' mp 165°);36ir 3430 (NH), 1735 (urethane carbonyl), 1710 em-' (ketone); pmr (CDCly) 8 4.13 (32) G. I. Poos, G. E. Arth, R . E. Beyler, and L. H. Sarett, J . Amer. C h e m . Sac. ,TS,422 (1953). (33) H. 0. House and V. Kramar, J . Org. Chem.. 27, 4146 (1962). (34) T h e ir and pmr spectra mere identical with copies of spectra of the alcohol kindly forwarded by D r . Danishefsky. (35) A . I. Vogel, "Practical Organic Chemistry," 3rd ed, Longmans, Green and Co., London, 1962, p 264. (36) I n a recent letter Dr. Danishefsky has conceded t h e possibility of having confused the melting points of the epimers lad and 19d. R e reported*' t h e melting point for 19d as 145'.
n h R R I N G T O N AND S C H X A L Z L
(br t , J = 6.5 Hz, 2, CII methylene), 1.14 (9, 6, two tertiary methyls), 0.96 ( 8 , 3, tertiary methyl), 0.92 (d, J = 6.5 He, 3, CS methyl). Anal. Calcd for CzzH3103N:C, 73.91; H, 8.74. Found: C, 74.24; H , 8.89. Preparation of Tosylate 18c.-The alcohol 18a (0.25 g) was treated with 0.60 g of p-toluenesulfonyl chloride in 18 ml of pyridine at - 15" for 12 hr. Ten drops of water were then added and the reaction mixture was left for an additional 45 min at -15". After addition to excess dilute HC1 at 0", the reaction mixture was extracted with hexane. The extract was washed with dilute aqueous sodium carbonate and water and then dried over anhydrous sodium sulfate. Evaporation of solvent yielded 0.38 g (927,) of the crude tosylate 18c which Crystallized from benzene-hexane as colorless prisms: mp 99-100"; ir 1710 cm-1 (ketone); pmr 6 3.95 (m, 2, CH methylene), 2.47 (s, 3, aromatic methyl), 1.08 (s, 3, tertiary methyl), 1.00 (s, 3, tertiary methyl), 0.83 (s, 3, tertiary methyl), 0.83 (d, J = 6.5 Hz, 3, Cg methyl). Anal. Calcd for CZ2Ha2O4S:C, 67.32; H , 8.22; S, 8.15. Found: C,67.62; H,8.38; S,7.90. Preparation of Iodide 18e .-Following an established prog of the tosylate 18c was stirred with 1.5 g of ~ e d u r e , ~0.50 ' sodium iodide in 20 ml of acetone at 20" for 20 hr, after which time a considerable quantity of sodium tosylate had precipitated. The reaction mixture was poured into water and the iodide was extracted with hexane. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to yield the crude iodide Me, which was purified by chromatography over 40 g of neutral activity I alumina. Elution with hexane-ether (9: 1) yielded 0.40 g (90%) of the iodide 18e as a colorless liquid. Vpc analysis showed a single peak on 37, SE-30 at 170": ir 1710 em-' (ketone); pmr S 3.6j-2.8 (very complex m, 2, C11 methylene), 1.10 (s, 3, tertiary methyl), 1.06 ( 9 , 3, tertiary methyl), 0.93 (s, 3, tertiary methyl), 0.86 (d, J = 6.5 Hz, 3, Cg methyl). When an attempt was made to obtain an analytical sample of 18e, either by preparative vpc or by microdistillation, it decomposed slightly to give a pale yellow oil, which analyzed about 2% high for carbon and 0.870 low for iodine. Attempted Cyclization of 18e with Magnesium and Mercuric Chloride.-The iodide 18e (50 mg) in 1.5 ml of tetrahydrofuran which had been freshly distilled from sodium-naphthalene was treated with 15 mg of magnesium powder and 45 mg of mercuric chloride. The mixture was heated in a sealed flask at 80-90" for 2 hr and then poured into water. Extraction with hexane resulted in recovery of the iodide unchanged (pmr and vpc). Cyclization of Iodide 18e with Sodium.-A solution of 0.20 g of the iodide in 5 ml of tetrahydrofuran, which had been freshly distilled from sodium-naphthalene, was transferred to a thickwalled glass tube. Fine sodium sand (0.15 g), prepared by shaking molten sodium in paraffin oil, was added and the tube was sealed and heated at 90-100" for 4 hr. The surface of the metal became coated with a powdery deposit which soon crumbled and revealed the shiny metallic surface of the residual sodium. The tube was left overnight at 20°, the seal was broken, and the red solution was poured into water. After acidification with dilute HC1, the product was extracted with hexane. The extract was washed with water and dried over anhydrous sodium sulfate, and the solvent was evaporated to leave 0.12 g of a colorless oil. The ir spectrum of this crude product showed some free hydroxyl absorption (3610 em-1) and carbonyl absorption (1705 em-I). Analysis of the mixture by vpc showed it to contain two major products, A and B, which accounted for 62% of the total area under all the peaks (40 and 22%, respectively). When the reaction was carried out in more dilute solution (10-20 mg of iodide in 5 ml of tetrahydrofuran), a cleaner reaction product was obtained. Vpc analysis in this case showed A to constitute 45% of the total area and B 317,. The retention times of A and €3 on 57, DEGS at 120' were 6 and 2.5 min, respectively. A and B were isolated by preparative vpc on 107, Carbowax 20M at 200". The constituent A was a colorless semisolid which was readily purified by sublimation to give (&)-patchouli alcohol ( 2 ) : mp 46-47" (lit.27mp 39-40'); ir 3610 (free OH), 1380, 1370, and 1363 em-1 (methyls);38 pmr 6 1.06 (s, 6, two tertiary methyls), (37) R . S. Tipson, M. A , Clapp, and L. H. Cretcher, J . Ow. C h e m . , 12, 133 (1947). (38) A noteworthy feature of the i r spectrum of patchouli alcohol was these three strong, well-resolved absorptions. Presumably the "doublet" a t 1380 and 1370 cm. 1 mas due t o symmetric and asymmetric gem-dimethyl stretching vibratione.
J . Org. Chem., Vol. 37, No. 18,1972 2877
BICYCLO[2.3.2]OCTENES. VI 0.82 (s, 3, tertiary methyl), 0.80 (d, J = 6.5 Hz, 3, secondary methyl). The vpc retention time39 (5% UCON, 5 7 , DEGS) and ir and pmr spectra were superimposable on those of naturally occurring ( - )-patchouli alcohol.40 The mass spectrum was also identical with that of the natural product. Constituent B was the oily acyclic ketone 18g: ir 1705 (39) T h e synthetic material mas mixed with naturally occurring (-1patchouli alcohol and peak enhancement was observed on the two columns a t various temperatures. (40) Katurally occurring. (-)-patchouli alcohol, mp 56', was isolated from patchouli oil which was generously donated by Plaimar Ltd., Perth. T h e higher boiling fractions of the oil were chromatographed over neutral alumina to give patchouli alcohol of high purity.
cm-l (ketone); pmr 6 1.09 (9, 3, tertiary methyl), 1.07 (s, 3, tertiary methyl), 0.88 (s, 3, tertiary methyl), 0.86 (d, J = 6.5 Hz, 3, CSmethyl); mass spectrum m/e 222 (M+).
Registry No. -( *)-2, 5986-55-0; 4, 34996-60-6; 6, 34996-61-7; 7, 34996-62-8; 8, 34996-63-9; 9a, 34996-28-3; 9b, 34996-64-0; loa, 34996-65-1; lob, 34996-66-2; (=k)-14a,29450-72-4; (*)-14c, 2944820-2; (+)-15a, 29448-21-3; (&)-16, 34996-70-8; (&)-Ma, 21682-97-3; (*)-18c,34996-72-0; (&)-18d, 21683-01-2; (*)-Me, 34996-74-2; (=k)-18g,21682-98-4.
Studies with Bicyclo[2.2.2]octenes. VI.' The Total Synthesis of ( *)-Seychellene2 ROBERT N. MIRRINGTON* AND
I
